Strategies to prevent post-transplant relapse in acute myeloid leukemia and myelodysplastic syndromes.

Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Post-transplant treatment may provide a third anti-leukemic effect after conditioning-related cytotoxicity has waned and before graft-versus-leukemia immunity is fully established. Prophylactic maintenance is initiated in high-risk patients despite undetectable measurable residual disease (MRD), whereas pre-emptive treatment is triggered by the detection of MRD or declining donor chimerism. Hypomethylating agents (HMAs) are biologically attractive and feasible with post-transplant-adapted dosing, but prophylactic azacitidine did not improve relapse-free or overall survival in a randomized trial. Newer decitabine-based, oral HMA, and venetoclax-containing strategies require confirmation. FMS-like tyrosine kinase 3 (FLT3) inhibitors have the strongest prospective evidence in a molecularly selected population. The QuANTUM-First trial supports quizartinib throughout induction, consolidation, and continuation, including after transplantation, whereas the MORPHO trial directly evaluated post-transplant gilteritinib and identified its clearest benefit in patients with detectable peri-transplant FLT3-internal tandem duplication (FLT3-ITD) MRD. This review traces the evolution of relapse prevention strategies and proposes a practical framework integrating baseline risk, serial MRD assessment, targetable biology, immune intervention, and post-transplant feasibility.